Document Detail

ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis.
MedLine Citation:
PMID:  23318439     Owner:  NLM     Status:  MEDLINE    
Cyclin D1 deregulation is implicated in the genesis of multiple human cancers. Importantly, nuclear cyclin D1 retention during S-phase promotes DNA re-replication and subsequent genomic instability, providing a direct correlation between aberrant cyclin D1/CDK4 activity, transcriptional regulation and double strand DNA break (DSB) induction. Together, these molecular events catalyze the genomic instability necessary for neoplastic transformation. Given that replication-associated DNA damage is central to cyclin D1-driven neoplasia, inactivation of critical checkpoint mediators should augment cyclin D1-dependent tumorigenesis in vivo. To interrogate potential synergy between constitutively nuclear cyclin D1 expression and impaired DSB-induced checkpoint integrity, Ataxia Telangiectasia Mutated (ATM)-deficient mice harboring the Eμ-D1T286A transgene were generated and evaluated for tumor onset. Eμ-D1T286A/ATM-/- mice exhibit dramatically accelerated incidence of both B- and T-cell lymphomas relative to Eμ-D1T286A or ATM-/- control cohorts. Lymphomas exhibit clonal chromosomal alterations distinct from ATM-/- mice, which typically acquire translocations involving the Tcrα/δ locus during V(D)J recombination, and instead harbor alterations at the c-Myc locus. Collectively, these findings reveal an intricate relationship wherein nuclear cyclin D1/CDK4 drives genomic instability in the absence of ATM function and clonal selection of cells harboring alterations within the murine c-Myc locus, ultimately facilitating transformation and tumor formation.
L P Vaites; Z Lian; E K Lee; B Yin; A DeMicco; C H Bassing; J A Diehl
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-14
Journal Detail:
Title:  Oncogene     Volume:  33     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-01-03     Completed Date:  2014-03-03     Revised Date:  2014-08-05    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  129-33     Citation Subset:  IM    
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MeSH Terms
Ataxia Telangiectasia Mutated Proteins / deficiency,  genetics
Carcinogenesis / genetics*,  metabolism
Cell Nucleus / metabolism
Chromosome Aberrations
Cyclin D1 / metabolism*
Genomic Instability*
Lymphoma / genetics*,  metabolism
Mice, Knockout
Protein Transport
Proto-Oncogene Proteins c-myc / metabolism
Tumor Burden
Grant Support
Reg. No./Substance:
0/Ccnd1 protein, mouse; 0/Myc protein, mouse; 0/Proto-Oncogene Proteins c-myc; 136601-57-5/Cyclin D1; EC Telangiectasia Mutated Proteins; EC protein, mouse

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